Contemporary diagnostic medicine increasingly utilizes the quantitative measurement of biochemical markers. Many techniques for detecting protein and small molecule analytes clinically utilize antibody-based diagnostics. In general, immunodiagnostics are divided into two broad groups: 1) quantitative assays—prototypically ELISA and its variants—that require significant time (hours), expertise and equipment (spectrophotometer). These assays are typically performed in hospital clinical laboratories; and 2) qualitative assays—prototypically particulate labeled lateral flow immunochromatographic devices—that are rapid (minutes), and require no special expertise or equipment. These assays are suitable for both point-of-care (e.g. rapid strep, influenza) and home use (pregnancy, ovulation) applications, but generally lack the capacity to provide quantitative information.
In many instances, more rapid quantitative analyte information could be used for effective treatment decisions, for example, in cardiovascular medicine. Emergency departments are presented with nearly 8 million people annually with chest pain. The diagnosis of acute cardiovascular syndrome (ACS) can be exceptionally difficult; misdiagnosis rates have been estimated at as high as 12%, with resulting morbidity and mortality and significant associated malpractice costs. The quantitative determination of biochemical markers is already an important component of ACS diagnosis, but the currently available Enzyme-Linked Immunosorbent Assays (ELISA) or ELISA-type assays can delay the availability of information and reduce point-of-care diagnosis.
Although all ACS patients share a common underlying pathophysiology—atherosclerotic plaque rupture with varying levels of superimposed thrombus and/or distal embolization—they can present a remarkable constellation of symptoms. Classic ACS includes deep, generalized or poorly localized pain or discomfort in the chest or arm clearly associated with physical or emotional stress and relieved promptly by sublingual nitroglycerin. (Gibbons, Chatterjee et al. 1999) Many patients show no chest pain, but present with jaw, neck, ear or epigastric discomfort. Atypical presentation include recent onset indigestion, stabbing chest pain, nausea and vomiting, weakness, dizziness, palpitations, cold perspiration and a sense of impending doom.
Current practice evaluates ACS through electrocardiogram (ECG) and physical assessment. The 12-lead ECG is the primary diagnostic standard in the ER evaluation of ACS. (Timmis 1990) ST-segment elevation is the primary anomaly signifying underlying disease, but other deviations, such as ST-segment depression or deep T-wave inversion, identify high-risk patients. (Savonitto, Ardission et al. 1999) Unfortunately, many patients—perhaps as many as 40%—present with normal ECG. A range of alternative risk stratification algorithms have also been investigated; other than the widely used Goldman protocol (Goldman, Cook et al. 1988) and TIMI risk score, (Antman, Cohen et al. 2000). However, many provide a limited short-term prognostic value.
ACS diagnosis can be performed through the evaluation of biochemical markers. (de Winter, Koster et al. 1995) However, the utility of biochemical evaluation of cardiac patients can be substantially diminished by the clinical chemistry now used for diagnosis. Many assays now in use are variants of so-called sandwich immunoassays. (Van Blerk, Maes et al. 1992; Heeschen, Goldmann et al. 1999; Wu 1999; Oh, Foster et al. 2000; Venge, Lindahl et al. 2001) In such assays, a first antibody to an analyte of interest is affixed to a label that can be visualized either directly (metal or latex sol) or indirectly (enzyme). The presence of analyte is detected through the use of a second “capture” antibody, typically immobilized to some surface, forming a “sandwich” of labeled antibody/analyte/capture antibody. Through appropriate calibration, some versions of the assay can be quantified. However, the tests can be slow (hours) and require major instrumentation for read-out, a requirement incompatible with point-of-care use. Both requirements significantly delay the acquisition of important diagnostic information; although recent recommendations call for no more than 1-hour turnaround, this goal is frequently missed. (Wu, Apple et al. 1999; Alpert, Thygesen et al. 2000; Brunwald, Antman et al. 2002) Some attempts have been made to develop laboratory test sites near the ER, but a significant fraction of the delay is fundamental, and related to the nature of the assay. (Lee-Lewandrowski, Corboy et al. 2003) The development of rapid, accurate point-of-care diagnostic devices may have an impact on the diagnosis of ACS and on the resulting morbidity and mortality.